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Liquid-filled Gelatin Capsules

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Vol. 35(4) [July–Aug. 2009] of the USPC or the USP Council of Experts 1029

Liquid-filled Gelatin Capsules

Margareth R.C. Marques,ab Ewart Cole,c Dale Kruep,d Vivian Gray,e Dennis Murachanian,f William E. Brown,a Gabriel I. Giancasproa

ABSTRACT This Stimuli article provides an overview of the manufacturing, characteristics, and in vitro performance
evaluation of liquid-filled gelatin capsules. The intent of the article is to initiate discussion, to solicit public comments,
and to invite participation of interested parties in the efforts of the USP Biopharmaceutics Expert Committee in either
updating USP General Chapter Dissolution h711i or creating a new General Chapter that will address the particularities
and special approaches required to develop and carry out in vitro performance evaluations of liquid-filled gelatin
capsules.

HISTORY OF LIQUID-FILLED GELATIN CAPSULES  Improved content uniformity of low-dose active sub-
stances

Stimuli to the Revision Process

Initially capsules were used because it was simple to
formulate them as unit dosage forms for drugs in pow-
dered or granular form and because they provided an
easy-to-swallow container that effectively masked the
bitter taste of drugs. With the advent of pellet technology
that enabled modified drug release, capsules provided a
useful vehicle into which multiparticulates could be filled
without risk of modifying the release characteristics asso-
ciated with other processing methods such as compres-
sion of multiparticulates into tablets (1). Since the early
1980s technology has been available to permit accurate
dosing and sealing of liquids into hard gelatin capsules
(2–4).
Advantages of liquid- and semisolid-filled hard gelatin
capsules include:
 Improved bioavailability
 Reduced dust for handling potent compounds
 Process simplification for low-melting-point active
substances
 Enhanced stability
 Sustained release.
Unlike soft gelatin capsules, in which the fill and the
shell are manufactured in one operation, hard capsules
are manufactured and supplied to the pharmaceutical
manufacturer empty. The capsule first needs to be filled
and then sealed. Most modern capsule-filling machines
can be modified to allow hard gelatin capsules to be filled
with hot or cold liquids. Equipment requirements that al-
low industrial manufacture of liquid-filled capsules are re-
ported by Cole (5), and examples of some available
models are given in Table 1.

Table 1. Capsule-filling Machines for Liquid Filling of Hard Gelatin Capsules up to Production Scale
Machine Type Filling Action Approximate Filling Rate
(Capsules/h)
Robert Bosch GmbH Intermittent motion
GKF 1400 L 60,000
GKF 701 L 36,000
Harro Hoefliger GmbH Intermittent motion
KFM III-C 25,000
IMA Zanasi Division All intermittent motion
Zanasi 6/12 6,000–12,000
Zanasi 25/40 25,000–40,000
Zanasi Lab 8/16 8,000–16,000
Zanasi Plus 32,000–85,000
2E/48E/70E/85E
a
Documentary Standards Division, USP.
b
Correspondence should be addressed to Margareth R.C. Marques,
MSc, PhD, Senior Scientist, US Pharmacopeia, 12601 Twinbrook Park-
way, Rockville, MD 20852-1790, tel. 301.816.8106; e-mail mrm@
usp.org.
c
Consultant, Capsugel, Division of Pfizer, Switzerland.
d
Banner Pharmacaps, Inc.
e
Member USP Biopharmaceutics Expert Committee.
f
Capsugel, Division of Pfizer, USA.

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Stimuli articles do not necessarily reflect the policies Pharmacopeial Forum
1030 of the USPC or the USP Council of Experts Vol. 35(4) [July–Aug. 2009]

Table 1. Capsule-filling Machines for Liquid Filling of Hard Gelatin Capsules up to Production Scale
(Continued)

Machine Type Filling Action Approximate Filling Rate

(Capsules/h)
MG2 All continuous motion
MG Compact 6,000–96,000
MG Futura 6,000–96,000
Planeta 100 100,000
Qualicaps All continuous motion
F-5 4,000
F-40 30,000
F-80 60,000
F-120 90,000
F-150 120,000
Schaefer Technologies Inc. Semi-automatic
LF-10 10,000–25,000
Bonapace Intermittent motion
Stimuli to the Revision Process

IN-CAP 3,000

An essential part of a liquid-filling operation is the abil- water-soluble vehicles. Hydrophilic suspensions include
ity to effectively seal the capsule. Various methods are drugs suspended in hydrophilic vehicles such as poly-
available to seal hard gelatin capsules, and these have ethylene glycol.
been reviewed by Wittwer (6). The two most studied
methods are banding using a gelatin band as described GEL COMPOSITION AND MATERIAL PROPERTIES
by Bowtle (7) and sealing using a hydroalcoholic solution
as described by Cole (8, 9). Both methods are described
in USP General Information Chapter Pharmaceutical Do- Composition and Properties of
sage Forms, Capsules h1151i (10). Gelatin Raw Material

NOMENCLATURE Considerable interest lies in replacements for gelatin as

Liquid-filled capsules can be classified into two main
types based on the physical characteristics of the shell:
soft gelatin capsules or softgels, and hard gelatin cap-
sules or hardgels. Softgels have a thicker shell and typi-
cally exhibit a higher degree of elasticity because of a
greater amount of added plasticizer relative to gelatin.
Hardgel shells are thinner and more rigid than softgels.
Both soft and hard gelatin capsules basically are com-
posed of gelatin, a plasticizer, and water. For hardgels
water acts as the plasticizer, whereas softgels use high-
boiling-point polyols such as glycerol and sorbitol.
Although many parameters affect the physical and
chemical performance of the shell, the ratio of gelatin
to plasticizer primarily determines the rigidity, brittleness,
and dissolution performance of the shell.
Liquid-filled capsules also can be characterized by the
chemical properties of the fill material (hydrophobic-
based vs hydrophilic-based fill materials) or by the physi-
cal properties of the fill material (solution vs suspension).
Hydrophobic solutions include neat oils, combinations of
miscible oils, or drugs dissolved in oil vehicles. Hydropho-
bic suspensions include drugs suspended in oils or in oil–
wax mixtures, often referred to as semisolids. Hydrophilic
solutions may be neat liquids or syrups, combinations of
water-soluble liquids or syrups, or drugs dissolved in
a suitable capsule shell matrix, especially in the dietary
supplement industry that serves a large number of con-
sumers who are strict vegetarians and do not want to
consume articles derived from animal origin. In addition,
some consumers avoid consumption of products of por-
cine origin. Alternative suitable materials include nonani-
mal sources such as potato starch and carrageenans from
seaweeds, as well as synthetic hydrogels, and ongoing
research aims to improve the quality and reduce the cost
of these replacements. However, as previously noted,
gelatin is the material used to produce the shell matrix
for most of the liquid-filled capsule pharmaceutical pro-
ducts currently on the market. Consequently, this Stimuli
article focuses on products for which the fill material is
encapsulated in a gelatin-based shell.
Gelatin is obtained from the partial hydrolysis of col-
lagen, which is the most abundant animal protein in nat-
ure. Collagen is an insoluble, highly ordered fibrous
protein and is the primary fibrous component of bone,
skin, and connective tissue. The majority of pharmaceu-
tical gelatin is produced from collagen from bovine
bone, bovine hide, and porcine skin, although some re-
ports describe the use of the skin from poultry and fish.
Collagen is a highly structured protein. It consists of indi-
vidual polypeptide chains containing approximately
1000 amino acid units of which glycine, proline, hydrox-
yproline, and alanine constitute ~60%. The primary
structure is dominated by regions of repeating amino

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acid sequences rich in glycine, proline, hydroxyproline,
and alanine. These regions readily form left-handed he-
lices that make up most of collagen’s secondary struc-
ture. Although collagen contains minimal tertiary
structure, significant quaternary structure is formed
when the helical regions of three different protein chains
wind around each other in a right-handed superhelix,
forming a ropelike structure. This superhelix, also called
tropocollagen, is held together by hydrogen bonding
and creates a three-dimensional protein matrix. The re-
gions of the primary structure not involved in the helices
contain most of the amino acids with ionic side chains
such as lysine, arginine, glutamic acid, and aspartic acid.
These regions contribute to the stabilization of the three-
dimensional structure by entering into ionic and covalent
linkages between protein chains and forming the charac-
teristic collagen fiber (11).
As noted above and in USP–NF (12), gelatin is a pro-
duct obtained by the partial hydrolysis of collagen de-
rived from the skin, white connective tissue, and bones
of animals. The hydrolysis may be catalyzed by the addi-
tion of strong acid or base. Gelatin derived from acid-cat-
alyzed hydrolysis is referred to as Type A, and gelatin
derived from base-catalyzed hydrolysis is referred to as
Type B. The main difference between gelatins derived
from these two processes is that the gelatin derived from
the acid-catalyzed process typically exhibits an isoelectric
point (pI) of approximately 7–9, whereas the pI of gelatin
obtained from the base-catalyzed process is typically
4.7–5.4. The lower pI resulting from the treatment with
base is due to the hydrolysis of the amide groups of glu-
tamine and asparagine, creating glutamic acid and as-
partic acid. Because of the manufacturing process used,
gelatin molecules exhibit significant polydispersity: The
molecular weight of individual molecules typically ranges
from 15,000 to 250,000. Gelatin maintains many of the
chemical and physical properties of collagen, the most
important of which is its ability to form superhelices
and to associate into a three-dimensional matrix. For gel-
atin this is a thermally reversible process at relatively low
temperatures and is an important reason why gelatin has
been the material of choice for providing the shell matrix
of liquid-filled capsules.
Gelatin is graded primarily on the strength of the gel it
forms, and, depending on the process used and the tis-
sue source, noticeable differences in strength are appar-
ent among suppliers and even between lots from the
same supplier. Consequently, controlling the strength
of the gel from batch to batch (measured as bloom
strength) is a key to obtaining a consistently performing
product. Bloom strength is a measure of the ability of a
given weight of gelatin to set up in water under con-
trolled conditions and is a function of the molecular
weight of the gelatin molecules, the concentration of
the gelatin in the gel, and the pH of the gel. It is a mea-
sure of the resultant gel’s resistance to compression and
is reported in bloom-grams or simply grams. Bloom
strength increases when the gelatin concentration in
the gel increases, when the average molecular weight
of the gelatin increases, and when the pH of the gel ap-
proaches neutrality (from either direction). In addition,
as bloom strength increases the cost of gelatin increases
# 2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
1031
and gel dissolution rate decreases. Bloom strength also
can have an effect on the clarity and color of liquid-filled
capsules. For gelatin with higher bloom strength, less
gelatin is needed to produce a suitable shell, which re-
sults in a clearer shell and a reduced need for colorants
and dyes in order to produce the desired hue. Although
gelatin with bloom strengths ranging from 50 to 300 is
available, most gelatins used in the manufacture of liq-
uid-filled capsules have a bloom strength of approxi-
mately 150–200 for softgels and 220–280 for hardgels.
Gelatin manufacturers commonly blend different sublots
of gelatin to meet bloom requirements.
Composition and Properties of the Gel Mass and
Finished Shell
In its simplest form the shell of a liquid-filled capsule is
prepared from a molten gel mass that is composed of
gelatin and a plasticizer dissolved in an aqueous vehicle.
For hardgels water acts as both the plasticizer and the ve-
Stimuli to the Revision Process
hicle. For softgels small polyhydroxy compounds such as
glycerol, sorbitol, and maltitol typically are used as plas-
ticizers. Normally, during the preparation of the gel mass
gelatin is first hydrated in a measured amount of excess
water before plasticizer is added and the mass is heated
to complete the solution. Less frequently, gelatin may be
added directly into hot water and dissolved immediately.
The gel mass for hardgels normally contains about 30–35
parts gelatin and 65–70 parts water by weight. The gel
mass for softgels commonly starts out at approximately
40–45 parts gelatin, 30–35 parts plasticizer, and 20–30
parts water. However, depending on the desired perfor-
mance traits of the shell, the size of the shell, and the
composition of the fill material, the gelatin:plasticizer ra-
tio for softgels may vary from 1.0 to 3.0. Other minor
components added to the gel mass may include color-
ants, flavors, stabilizers, buffers, and opacifiers.
Before the encapsulation process the gel mass is kept
warm (about 60 8C) and at a high water content so that it
remains pliable and free flowing, in some cases as long as
4 days. During this time the gelatin exists as single pro-
tein molecules in a random configuration and sheathed
by water molecules. The proteins slowly hydrolyze over
time at high temperatures, and this occurs more rapidly
the further the pH of the gel mass departs from neutral-
ity. This phenomenon may be detected by a decrease in
the viscosity of the gel mass.
For softgels the capsule shells are manufactured and
filled in one continuous operation. The warm gel mass
is allowed to flow onto a chilled rotating casting drum
where gelation begins to occur and a gel ribbon is
formed. As the temperature of the gel decreases below
40 8C and lower, the gelatin molecules begin to re-form
the secondary structural characteristics that were exhib-
ited by the parent collagen fibers and were held in place
by hydrogen and ionic bonding. The degree to which
the superhelices form depends on how fast the gel cools
and to what extent the plasticizer associates with the gel-
atin. The plasticizer breaks up the ordered structure,
thereby increasing elasticity. At this time the gel also be-
gins to evaporate water, the rate of which also affects the
final association and alignment of the gelatin molecules.
 STIMULI TO THE REVISION PROCESS
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1032 of the USPC or the USP Council of Experts Vol. 35(4) [July–Aug. 2009]
Within minutes a relatively wet, elastic gel ribbon is tin concentration and gel strength, the rate and extent of
formed and is routed through lubricating rollers on its water loss determine the hardness and brittleness of the
way to the dies and wedge on the encapsulation ma- capsules, their ability to undergo dissolution, and their
chine. At the wedge two opposing gel ribbons are tendency to stick to each other. In the completed pro-
brought together on the dies, and a sandwich is created duct hardgel shells contain approximately 13%–16%
as the fill material is injected between the ribbons. As the water, and softgels contain approximately 6.5%–8.0%.
fill material is injected between the ribbons the latter are Gelatin is a hygroscopic material, and the relationships
pressed into the die cavities, thereby creating the cap- among relative humidity, gelatin moisture content, and
sule. As the dies come together the two halves of the cap- hard gelatin capsule properties are shown in Figure 1
sule shell are sealed. This process is assisted by the (13). Kontny and Mulski (14) also have studied the rela-
wedge, which is held at slightly elevated temperature tionship between relative humidity and brittleness of
(37–40 8C) to soften the ribbon. The dies finish the en- hard gelatin capsules. Because certain solvents are
capsulation process by cutting the capsules from the rib- known hydrophilic agents, it is particularly important to
bon. Next, the capsules begin the drying process and are monitor the mechanical properties of liquid-filled cap-
carefully dried to their final moisture content. Drying is sules stored under various conditions of temperature
performed under conditions of highly controlled tem- and relative humidity. Methodology to determine the
perature, relative humidity, and airflow. Along with gela- compatibility of fill materials has been described (15).
Stimuli to the Revision Process

Figure 1. Relative Humidity (RH), Gelatin Moisture Content, and Hard Gelatin Capsule Properties.

Stability and Reactivity of Gelatin
At room temperature the shells of fully dried capsules
are relatively effective at protecting the fill from oxygen
and its effects, and when an opacifier such as titanium
dioxide is added to the shell it can prevent photodegra-
dation of the fill. In addition, the low water content of the
shell does not promote microbial growth. Bacteria,
yeasts, and molds require high water content of at least
0.80% (w/w), and the water content of capsule shells
typically is less that half of that. However, it must be
stressed that capsule shells are not unreactive, physically
or chemically. As storage conditions change in tempera-
ture and humidity, so too does the gelatin matrix in the
shell. As temperature and humidity increase the shell ab-
sorbs moisture, and the gelatin molecules assume addi-
tional freedom of movement. The sol–gel transition
temperature for many gel formulas occurs just above
40 8C. Stress from temperature and relative humidity
can result in weakened seams, leaking, and their capsules

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Vol. 35(4) [July–Aug. 2009] of the USPC or the USP Council of Experts 1033
sticking together. Recommended storage conditions of found to be rapid and to be equivalent to drug release
the final product are typically 15–30 8C and 30%–60% from fresh nonstressed capsules (21). Bioequivalence be-
relative humidity, or standard room temperature condi- tween stressed and unstressed acetaminophen hard and
tions. Brief excursions outside of these conditions are soft gelatin capsules also has been established (22).
rarely cause for concern. These findings have led to the acceptance of a two-tier
Another phenomenon seen in capsules, especially soft- dissolution test using enzymes (23). Techniques to moni-
gels, is extensive cross-linking of the gelatin, which can tor any potential incompatibility between the fill material
occur during storage and can result in the formation dur- and the capsule have been described (15).
ing dissolution testing of swollen, rubbery water-insolu-
ble membranes known as pellicles that may act as a APPLICATIONS AND FORMULATION STRATEGIES
barrier to drug release. A pellicle is a thin clear membrane FOR HARD GELATIN CAPSULES
of cross-linked protein surrounding the fill or the capsule
and preventing the fill from being released. This cross- Table 2 summarizes drug characteristics for which liq-
linking involves strong chemical linkages beyond simple uid-filling technology is applicable. The important factors
hydrogen and ionic bonding between gelatin chains, during a liquid-filling operation are temperature and vis-
and the linkages formed can affect the thermal reversibil- cosity of fill material and, in the case of a suspension, the
ity of the gelatin shell. One of the strongest and most particle size of the suspended drug. In principle, any ex-
common types of cross-linking involves the covalent cipient found to be compatible with the gelatin shell can
bonding of the amine group of a lysine side chain of be used, but in a manufacturing environment the vis-
one gelatin molecule to a similar amine group on an- cosity of the fill material is important. If the viscosity is

Stimuli to the Revision Process

other molecule. This reaction generally is catalyzed by too low, splashing of the bushings may contaminate
trace amounts of reactive aldehydes (16, 17). Formalde- the area of overlap between the capsule body and cap,
hyde, glutaraldehyde, glyoxal, and reducing sugars are preventing the capsule from being effectively sealed. Ab-
the most common catalysts. The covalent bonding pro- sence of a clean break during dosing (stringing) can have
duced with this type of cross-linking is, for all practical the same effect. Recommended guidelines for dosing li-
purposes, irreversible, and dissolution of the shell must quids or semisolids into hard gelatin capsules are given in
involve the breaking of other bonds, e.g., by enzyme- Table 3. Excipients that are solid at room temperature but
mediated breaking of peptide bonds in protein chains. melt at temperatures up to 70 8C are well suited for for-
It has been proposed that chemically modifying gelatin, mulating APIs, provided they yield the desired pharma-
perhaps by adding succininc acid groups to the lysine cokinetic and stability profiles. Bowtle (7) has described
side chains, may prevent or at least diminish aldehyde- a process for selecting bases for thermosetting formula-
mediated cross-linking. Another, weaker, type of cross- tions.
linking is complexation of free carboxylic acid groups
on two different gelatin molecules with trivalent metal Table 2. Drug Characteristics and Liquid-filling
ions, such as Fe3+ and Al3+. These cations may be found Technologies
in some of the dyes used as colorants or as low levels of
contaminants in excipients. Higher bloom gelatin, which Characteristic Refer- Examples of Mar-
normally is associated with higher quality, facilitates effi- ences keted Products
cient cross-linking because fewer links are needed to join Poorly soluble 24–30 Nifedipine (Aprical)
greater lengths of gelatin chains. Ibuprofen (Solufen)
Common causes of cross-linking include: Short half-life 31–37 Captopril (Captoril)
 Aldehydes present in active pharmaceutical ingredi- requiring frequent
ents (APIs), excipients, packaging materials, or de- dosing
gradants formed in situ during storage Low melting point 38 Oils of avocado and
 High humidity

soya (Piascledine)
Indirect catalysis in cross-linking reactions Danthron (Co-dan-
 Decomposition of a stabilizer in corn starch thramer)
(hexamethylenetetramine), which forms ammonia
Low dose/high po- 8, 31, Cytotoxic products
and formaldehyde, which in turn promote cross-link-
tency 38, 39 in development
ing reactions
 Rayon coilers that contain an aldeydic functional Critical stability 40–43 Vancomycin hydro-
chloride
group (18)
 (Vancocin)
Polyethylene glycols that may auto-oxidize to form
aldehydes
 UV light, especially in the presence of high heat and Other process-related factors include:
humidity (19, 20)  Excipient/drug stability over time
 Heat, which can catalyze aldehyde formation.  Temperature-dependent solubility of drug in lipid
 Aging/polymorphic characteristics of the lipid
Dissolution testing of capsules that are affected by
cross-linking can yield results that suggest an apparently
slower drug-release profile. However, in vivo disintegra-
tion of cross-linked capsules in healthy volunteers was

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1034 of the USPC or the USP Council of Experts Vol. 35(4) [July–Aug. 2009]
 Adequate characterization of the saturation/supersa- — Sunflower oil.
turation status of the drug in the lipid formulation in  Medium-chain triglycerides and related esters:
order to avoid drug ‘‘crashing out.’’ Optimally sa- — Capr ylic/capric triglycerides (Akomed E,
turation status should be determined when the for- Akomed R, Miglyol 810, and Captex 355)
mulation is at equilibrium with the shell — Medium-chain triglyceride (Labrafac CC)
 Stability in solution under stress — Propylene glycol diester of caprylic/capric acid
 The potential for aldehyde formation and drug de- (Labrafac PG)
gradation if hot melts are held for prolonged times — Propylene glycol monolaurate (Lauroglycol FCC)
at elevated temperatures — Fractionated coconut oil (Miglyol 812)
 The influence, if any, of the rate of cooling on the — Caprylic/capric/diglyceryl succinate (Miglyol
structure of certain excipients that may modify 829)
— Medium-chain diesters of propylene glycols (Mi-
drug-release characteristics from the matrix (43).
glyol 840)
— Partial ester of diglycerides with natural fatty
Table 3. Recommended Guidelines for Dosing
Liquids and Semisolids into Hard Gelatin Capsules acids (Softisan 645).
 Solubilizing agents, surfactants, emulsifying agents,
Parameter Recommendation and adsorption enhancers compatible with hard gel-
Temperature of fill ma- Maximum approximately atin capsules:{
terial 70 8C — Propylene glycol monocaprylate (Capryol 90)
Stimuli to the Revision Process

— Polyglycolized glycerides (Gelucire 44/14 and

Viscosity at the tempera- 0.1–1.0 Pa  s
ture of dosing 50/13)
— Polyoxyl-40 hydrogenated castor oil (Cremo-
Dosing characteristics Clean break from dosing
phor RH 40)
nozzle and absence of
— Glycerol monostearate/di-triglycerides + glycer-
‘‘stringing’’
in (Imwitor 191)
Particle size of suspended  50 mm — Glyceryl monocaprylate (Imwitor 308*)
drug — Glyceryl cocoate/citrate/lactate (Imwitor 380)
— Glyceryl mono-di-caprylate/caprate (Imwitor
As increasing numbers of poorly water soluble drugs 742)
enter the pipeline, so do the challenges of finding inno- — Isosteryl diglyceryl succinate (Imwitor 780 K)
vative ways of developing bioavailable and stable dosage — Glyceryl cocoate (Imwitor 928)
forms. In the dietary supplement industry, formulators — Glyceryl caprylate (Imwitor 988)
also are finding an increased interest in new liquid-en- — Oleoyl macrogol-8 glycerides (Labrafil M 1944
capsulated presentations of fat-soluble vitamins and li- CS)
pophylic products such as Co-enzyme Q10, lycopene, — Linoleoyl macrogolglycerides (Labrafil M 2125
or lutein that are prepared for improved bioavailability. CS)
Excipient suppliers, encouraged by potential opportu- — PEG-8 caprylic/capric glycerides (Labrasol)
nities, are developing new materials comprising mixtures — Lauric acid
of functional excipients. — Propylene glycol laurate (Lauroglycol 90)
A range of excipients have been tested and found to be — Oleic acid
compatible with hard gelatin capsules. They can be clas- — PEG MW > 4000
sified into three arbitrary groups: — Polyglycerol dioleate (Plurol Oleique CC 497)
 Lipophilic liquid vehicles — Polyoxyethylene-polyoxypropylene copolymer
 Semisolid lipophilic vehicles/viscosity modifiers for li- (Poloxamer 124 and 188)
pophilic liquid vehicles — Partial glycerides of hydroxylated unsaturated
 Solubilizing agents, surfactants, emulsifying agents, fatty acids (Softigen 701)
and adsorption enhancers. — PEG-6 caprylic/capric glycerides (Softigen 767)
These excipients are listed below: — Polyoxyethylene glyceryl trioleate (Tagat TO)
 Lipophilic liquid vehicles compatible with hard gela- — Polyoxyethylene(20)sorbitan monooleate
tin capsules* (Tween 80).
 Refined specialty oils: The excipients shown below are generally incompati-
— Arachis oil ble with hard gelatin capsules and should be avoided in
— Castor oil high concentrations. They may, however, be used in
— Cottonseed oil mixed systems (i.e., systems that involve nonreactive, ac-
— Maize (corn) oil ceptable excipients for hard gelatin capsules). In such
— Olive oil cases the critical concentration that would lead to incom-
— Sesame oil patibility must be determined experimentally. The com-
— Soybean oil
* {
Quality may vary among suppliers and also from batch to batch and Quality may vary among suppliers and also from batch to batch and
should be routinely checked. The thermal history of excipients should should be routinely checked. The thermal history of excipients should
be recorded during manufacturing. be recorded during manufacturing.

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patibility of the final formulation, including the API, must
be monitored as part of the routine development pro-
cess.
Excipients that are incompatible with hard gelatin cap-
sules in unmixed systemsz:
Ethanol
Hydrogenated polyoxyl castor oil (Cremophor EL)
Glycerin (with a content > 5%)
Glycofurol 75
Medium-chain mono- and diglycerides (Akoline
MCM and Capmul MCM)
Glyceryl monocaprylate (Imwitor 308*)
PEGs of MW < 4000
N-methyl-2-pyrrollidone (Pharmasolve)
Propylene glycol
Sorbitan monooleate (Span 80)
Diethylene glycol monoethylether (Transcutol P).
APPLICATIONS AND FORMULATION STRATEGIES
FOR LIQUID-FILLED CAPSULES
Hard Gelatin Capsules
Liquid-filled capsules often are used to deliver APIs
such as oily or waxy substances that are not easily formu-
lated in solid delivery systems. Substances that are easily
formulated in solid dosage forms also may be formulated
in liquid-filled capsules for product line extensions and to
improve product performance or bioavailability. Refor-
mulation may include coating the capsule or adding in-
gredients into the shell to produce delayed- or extended-
release properties. Chewable products, which often re-
quire additional texture and flavor components, are
being developed.
With some limitations and exceptions, most of the ex-
cipients used to develop pharmaceutical solutions or
semisolids can be used for developing fill materials for liq-
uid-filled capsules, including emulsifiers and liquid poly-
mers. Hydrophilic substances can be formulated into a
capsule filling material, but water or low molecular
weight alcohols should be kept at or below 10%. Higher
levels may initiate erosion of the shell or cause appear-
ance problems because of diffusion and evaporation
from the fill material and/or the shell. Levels of glycerol
and other plasticizers should be kept to a minimum or
should be accounted for in the shell formula because
they can diffuse into the shell and produce unacceptably
soft capsules. Conversely, glycerol in the shell may mi-
grate into very hydrophilic fill material, and it may be
necessary to add some glycerol to the fill material to es-
tablish equilibrium.
Soft Gelatin Capsules
The fill material cannot be so thin that it leaks around
the pump and wedge assembly, but it must not be so vis-
cous that it cannot flow through the lines to the encap-
sulation pump or be accurately pumped into the capsule.
z
Mixed systems may permit use of some of these excipients in low con-
centrations, but the limit of the excipients listed here must be deter-
mined experimentally.
# 2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
1035
Thicker fill materials may be warmed to reduce viscosity,
but the temperature must be kept below 35 8C so that
integrity of the gelatin shell and the sealing operation
are not compromised. Both shell and fill excipients
should be controlled for levels of known cross-linking
agents such as formaldehyde and reducing sugars. Shell
and fill excipients should be controlled for particle size
(normally  170 mm or 80 mesh) and the presence of fi-
bers. Large particles in the shell and seams can create
weak points where leaking can occur, and a fiber that
crosses a seam can act as a wick that facilitates leaks.
A few processing variables and shell formulations
should be controlled with a high degree of precision be-
cause certain fill materials behave unpredictably if pro-
cessing steps are not well controlled. Die speeds that
are too slow or too fast may create poor seam quality
and result in leaking capsules. Gel ribbon thickness must
be precisely controlled to ensure consistent product ap-
pearance and dissolution performance within and be-
tween lots of product. The rate and extent of capsule
Stimuli to the Revision Process
drying probably is the most important processing para-
meter. Drying parameters must be individually deter-
mined for each combination of shell and fill material,
and they must be consistently maintained within and be-
tween lots of product. Removal of too much water may
result in hard, brittle capsules that have a higher propen-
sity to develop cracked shells and/or require a longer
time for dissolution. Not enough drying results in cap-
sules that are too soft and that may weep, become tacky,
and/or tightly stick to each other. If the drying conditions
remove water too rapidly—caused by high drying tem-
peratures, very low relative humidity, and/or high air-
flow—case hardening may occur. Case hardening takes
place when the exterior surface of the capsule dries very
rapidly and forms a temporarily seal that prevents further
egress of moisture from the fill and shell. During case
hardening capsule hardness is temporarily increased,
but when the capsule is removed from the rapid drying
conditions excess moisture within the fill and shell diffuse
into the hardened surface. Thus the capsule emerges as a
too-soft, under-dried product.
DISSOLUTION PROCEDURE DEVELOPMENT
Purpose of Test
Among the reasons for measuring the dissolution per-
formance of liquid-filled capsules is to ensure the quality
of the product. A well-designed dissolution test indicates
when significant batch-to-batch variations occur and is a
surrogate for demonstrating manufacturing consistency
or significant changes in the dissolution performance of a
single batch during the product’s shelf life (e.g., gelatin
cross-linking) (44–47). Dissolution performance also can
be used as a research tool. For example, during the devel-
opment of a generic drug product the dissolution perfor-
mance of various formulations may be compared to that
of the reference listed drug to ensure that product devel-
opment is proceeding correctly. Dissolution tests also are
used to evaluate formulation design and storage condi-
tions (48). More recently, dissolution testing has been
 STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies
1036 of the USPC or the USP Council of Experts
used to make in vitro/in vivo correlations (IVIVC) be-
tween different products or between variations of the
same product.
Although conceptually designed for tablets, dissolu-
tion testing has been extended to encapsulated drug-de-
livery formulations. In these systems, the drug is
presented, often solubilized, in a liquid or semisolid for-
mulation, and the relationship between solid drug disso-
lution and ultimate bioavailability has been
disconnected. When a dissolution test is conducted on
this type of formulation, the result is either a dissolution
of the contents or the formation of an emulsion and is
complicated by the sensitivity of these emulsions to their
physical environment. Further, many of these formula-
tions undergo digestive processes in vivo resulting in a
breakdown of the formulation that is not mimicked in a
dissolution test. Thus, the translation of the concept of
dissolution testing to bioavailability of lipid-based drug
delivery formulations is confusing. Nevertheless, at-
tempts to design dissolution tests for lipid-based systems
Stimuli to the Revision Process
have been reported and discussed (49–52).
The ‘‘dissolution’’ of a encapsulated liquid formulation
depends on its design. The gelatin capsule must rupture
to release its contents. Rupture is a process more relevant
than complete disintegration, which usually measures
the dissolution of the shell. Therefore, for dietary supple-
ments, a general rupture test was recently incorporated
in USP General Chapter Disintegration and Dissolution of
Dietary Supplements h2040i (53), where disintegration
for soft shell capsules is required. What happens next de-
pends on the composition of the formulation. For water-
based formulations containing concentrated solutions,
the rupture of the shell may be the only relevant step
for bioavailability and IVIVC. For this reason, several
monographs in USP contain rupture tests as the only per-
formance standard for these dosage forms. For lipid-
based formulations, which often are less dense than the
aqueous medium, the release from the capsule is buoy-
ancy driven.
If the formulation has been designed to be self-emulsi-
fying, the formulation will efficiently disperse into most
aqueous media. Formulations such as those consisting
simply of a triglyceride with no additional cosolvent or
emulsifier will rapidly float to the top of the vessel. The
assay results from a dissolution test in this situation pro-
vide the rate of extraction of drug from this floating layer.
As is the case with dissolution tests for traditional tablets,
the variables to consider are rotation speed, surfactant
type and concentration, medium pH, and apparatus.
Because ‘‘drug release’’ and its connection with bioa-
vailability are difficult to define, alternative tests may be
useful to better guide the dosage form design. These
tests include dispersibility, measurement of globule size
for emulsions, micelle formation, lipolysis, precipitation
on dilution in biorelevant media, phase behavior studies,
and burst tests to detect gelatin crosslinking (52, 54, 55).
Design of the Test
Developing a suitable dissolution test procedure for a
liquid-filled capsule depends on the physical and chemi-
cal properties of the drug substance and the product.
# 2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
Vol. 35(4) [July–Aug. 2009]
Developing a dissolution method for most liquid-filled
capsules that contain a hydrophilic fill material typically
follows the approach used for solid oral dosage forms.
It may be possible to use disintegration as the perfor-
mance test if the drug is already dissolved in the hydro-
philic matrix because rupture of the shell to release the
capsule content is the limiting step (49, 56). Dissolution
testing should be required if the drug is dispersed as a
suspension or emulsion in the hydrophilic matrix. FDA’s
Guidance for Industry—Dissolution Testing of Immediate-re-
lease Solid Oral Dosage Forms is a general resource that
lists the types of media and equipment settings that are
acceptable from a regulatory standpoint (57). The first
step involves identifying a dissolution medium or several
media candidates that provide sink conditions, pre-
ferably using physiologically relevant media, for the drug
product. At minimum, the medium selected must pro-
vide sink conditions for the drug, must not interfere with
the activity of enzymes used to overcome crosslinking of
gelatin in Tier 2 tests, and must not show negative inter-
actions with the formulation. Next, during preliminary
trials the apparatus, media, media volume, agitation rate,
and other test parameters are varied to determine what
effect each has on the dissolution performance of the
product. A statistical matrix design can assist in identify-
ing critical parameters for a procedure that will consis-
tently provide a percentage dissolved of approximately
75%–80% of label claim within 30–45 min. Testing aged
and/or stressed capsules typically provides valuable in-
sight into a product’s dissolution performance.
Developing a suitable dissolution procedure for liquid-
filled capsules containing a hydrophobic matrix often
poses considerable challenges and requires a creative ap-
proach. Typically problems are encountered when one
tries to identify sink and agitation conditions for disper-
sing the fill material and solubilizing the drug. This is
especially the case for suspensions and waxy paste-filled
products. The ‘‘release’’ profile from hydrophobic ma-
trices is sensitive to the solubility of both the drug and
the matrix in the medium, as well as the relative partition-
ing of the drug between the matrix and the medium. Be-
fore choosing the apparatus and agitation intensity,
formulators must determine which media will disperse
the fill and dissolve the drug. Profiles that relate drug so-
lubility to media pH and ionic strength may be con-
structed. Surfactants available for testing include the
following:
 Polysorbates (Tween)
 Sodium dodecyl sulfate (sodium lauryl sulfate)
 Lauryl dimethyl amine oxide
 Cetyltrimethylammonium bromide
 Polyethoxylated alcohols
 Polyoxyethylene sorbitan
 Octoxynol (Triton X100)
 N,N–dimethyldodecylamine–N–oxide
 Hexadecyltrimethylammonium bromide
 Polyoxyl 10 lauryl ether
 Brij 721
 Bile salts (sodium deoxycholate and sodium cholate)
 Polyoxyl castor oil (Cremophor)
 Nonylphenol ethoxylate (Tergitol)
 Cyclodextrins
 STIMULI TO THE REVISION PROCESS
Pharmacopeial Forum Stimuli articles do not necessarily reflect the policies
Vol. 35(4) [July–Aug. 2009] of the USPC or the USP Council of Experts
 Lecithin
 Methylbenzethonium chloride (Hyamine) (58, 59).
Although it is frequently used to improve the solubility
of poorly soluble drugs in dissolution tests of tablets, so-
dium dodecyl sulfate should be considered only in the
absence of other alternatives because it readily denatures
enzymes that are used to overcome crosslinking in Tier 2
dissolution tests (60, 61). Use of pancreatin, which has
lipase activity, may help to increase the dissolution rate
not only because it hydrolyzes triglyceride matrices but
also because of the additional surfactant effect derived
from the resulting fatty acid salts.
Initial efforts attempt to identify suitable surfactants,
concentrations, and pH conditions that provide sink con-
ditions in an environment that ensures suitable stability.
Then formulators can evaluatie the effect of these condi-
tions on the formulation. During a dissolution test of a
lipid-filled capsule, the gelatin capsule opens and the li-
pid-based formulation is released. The resulting fluid jet
breaks up into droplets, and if the formulation is not so-
lubilized by the medium it often floats to the top of the
vessel. The fluid jet develops due to interfacial forces, and
droplet break-up occurs due to Rayleigh–Taylor instabil-
ity and the shear of mixing. Important physical proper-
ties include the density of the fluid, viscosity, and
interfacial tension between the fill and the medium.
However, upon dilution the formulation may undergo
phase transitions that may affect the viscosity, density,
and interfacial tension.
Simple visual evaluation can be used to screen the in-
teractions between surfactant solutions and formulations
by preparing blends of varying composition that span
the range from the neat formulation to a final dilution
in the surfactant medium that represents the expected
dilution in a dissolution test (e.g., 1 part in 250 parts
aqueous). Complete solubilization of the formulation will
provide a more robust dissolution test. When the formu-
lation is not solubilized by the medium, the dissolution
profile is a measure of the extraction of the drug from
the matrix and is influenced directly by the surfactant
concentration and the rotation speed of the apparatus.
Any surfactant–formulation combinations that form vis-
cous phases at intermediate dilutions should be used
with caution because they may negatively influence ex-
traction of the compound or the rate of solubilization of
the formulation and extend the ‘‘release’’ profile. Catio-
nic surfactants should be avoided in formulations that
contain fatty acids because of their propensity to form in-
soluble precipitates.
The dissolution profile obtained for a lipid-based for-
mulation in a given medium is designed for that particu-
lar formulation. This specific dissolution procedure
probably cannot be used to compare drug product re-
lease from several different formulations to predict in vivo
performance. Such a comparison should be made only
with a complete understating of the dispersion behavior
of the formulations and their interactions with the me-
dium. Often other measurements such as rate of disper-
sion, particle size, and lipolysis provide appropriate
predictors of physico-chemical phenomena for correla-
tion with in vivo performance. Depending on the nature
of the drug and its mechanisms of absorption, it may be
# 2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
1037
helpful to use dissolution conditions that mimic the in
vivo environment. Such conditions include the use of
specific enzymes to transform the drug into the entity
that will be absorbed in vivo (62) or to affect excipients
in a manner that modifies the in vivo release of the drug
from the matrix.
Regulatory bodies discourage the use of organic co-
solvents to improve sink conditions, and thus co-solvents
should be employed as a last resort.
Procedures for sampling and analysis of aliquots are
similar to those for traditional dissolution tests. Some pre-
cautions must be taken to avoid disturbance of parti-
tioned formulations. Disruption or sampling of the
floating layer will result in anomalously high release mea-
surements and significant variability. Further, floating
material or emulsion droplets can accumulate around
the shaft of the paddle or basket, which can result in ra-
dial concentration gradients. Such gradients can lead to
variability if sample position is not controlled.
Delayed-release and enteric-coated capsule products
Stimuli to the Revision Process
are developed as line extensions, therapeutic improve-
ments, and protection for acid-labile drugs. Because of
the special claims and requirements of these products
the dissolution test conditions in USP General Chapters
Dissolution h711i and Drug Release h724i are used (63).
Deviations from h711i or h724i are rare, but the addition
of surfactants, bile salts, or other solubilizing aids may be
justified for drugs that present poor water solubility.
Selection of Apparatus
As is the case with solid dosage forms, baskets (USP Ap-
paratus 1) and paddles (USP Apparatus 2) are most often
chosen as the dissolution apparatus for gelatin capsules,
and both have been used successfully. However, with liq-
uid-filled capsules baskets may not be suitable in certain
instances. As a capsule breaks down the gelatin from the
shell may clog the basket’s mesh, and, with very hydro-
phobic fill materials, oil phase released from the capsule
may not disperse into fine enough droplets in the basket
to efficiently pass through the mesh. Occasionally, the
capsule and its contents may float in the dissolution med-
ia. In these instances wire coils can be wound around the
capsules, or commercially available sinkers can be used to
encase the capsules to hold them on the bottom of the
vessel and to allow the fill to become exposed to more of
the medium. In rare instances the capsule shell may stick
to the basket or the bottom of the vessel. The reciprocat-
ing cylinder (USP Apparatus 3) may overcome this pro-
blem because of its different mechanism of agitation.
Also, USP Apparatus 3 may be a more appropriate system
for generating IVIVC data than the basket or paddle
when one is testing liquid-filled capsules (64). However,
USP Apparatus 3 has a tendency to generate foam when
surfactants such as sodium lauryl sulfate are added to the
media. The rotating bottle apparatus may be an alterna-
tive that overcomes this problem. For drugs formulated
in soft gelatin capsules, an IVIVC was established using
the rotating dialysis cell method (65). This cell is placed
into a normal USP dissolution vessel. The cell encloses a
small volume (maximum 30 mL) of inner fluid by means
 STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies Pharmacopeial Forum
1038 of the USPC or the USP Council of Experts Vol. 35(4) [July–Aug. 2009]
of a dialysis membrane, and it can simulate the transfer of the gel. To address this issue formulators can use proteo-
drugs from the intestinal lumen (inside the cell) to tissues lytic preparations that contain pepsin or pancreatin and
(outside the cell) (66–68). certain enzymes as additives to dissolution media when
New dosage forms may require new approaches to cross-linking occurs in gelatin shells (23, 75). Evaluation
using compendial apparatus. For example, floating do- of the amount of enzymes is necessary in such cases and
sage forms have been investigated as a means of there may be circumstances in which the amount of en-
prolonging retention in the stomach in order to maintain zyme added currently recommended in USP 31 (23) may
sustained release. Such dosage forms may use a delivery be insufficient. Occasionally, liquid-filled capsules may
system that consists of a biphasic gelatin capsule that float in the dissolution medium, but this can be over-
contains a rapid-release component such as a lipophilic come if the capsule is held loosely in a sinker or if a wire
drug dissolved in an appropriate lipophilic solvent and coil is wound around the capsule. The use of commer-
a sustained-release solid erodible matrix that contains cially available sinkers is preferred and is strongly recom-
an emulsifier. To demonstrate the biphasic release char- mended to ensure consistent results between
acteristics of this delivery system, USP Apparatus 2 (pad- laboratories and between tests. Technology transfer stu-
dles) was modified in such a way that the top of the dies have identified differences that were not related to
paddle blade was just breaking the surface film of the dis- sample performance but rather to the techniques used
solution medium (69–71). in different laboratories to prevent samples from floating.
The use of USP Apparatus 4 (flow cell) is another suit- Liquid-filled capsules are useful dosage forms for deli-
able alternative for the dissolution test of liquid-filled cap- vering oily or waxy pharmaceutical preparations, but, as
sules, mainly for drugs with poor solubility (72, 73). USP discussed previously, obtaining sink conditions with uni-
Stimuli to the Revision Process

Apparatus 2 and Apparatus 4 were compared for dissolu- versally accepted dissolution media may be a challenge.
tion of soft gelatin capsule formulations of a poorly This challenge is compounded if cross-linking occurs be-
water-soluble amine drug. During testing with 0.01 N cause surfactants normally used to disperse the fill ma-
hydrochloric acid containing 0.25% polysorbate 80, terial and solubilize the drug may tend to diminish the
both apparatus gave similar dissolution profiles. Appara- protease activity of pepsin and pancreatin. This problem
tus 2 tended to give a faster rate of dissolution, but Ap- has recently been solved with a two-stage dissolution ap-
paratus 4 was better able to distinguish between proach: The dissolution was performed according to a
different formulations (74). procedure involving 800 mL of 0.1 N HCl with the addi-
Table 4 gives a summary of the dissolution conditions tion of pepsin to initiate hydrolysis of the pellicle. After 25
that formulators should consider when developing a dis- min, 100 mL of a sodium lauryl sulfate solution in 0.1 N
solution test for liquid-filled capsules. HCl was added to complete the dispersion of the fill and
solubilize the active ingredient. Samples were taken for
Table 4. Dissolution Conditions That Should Be analysis 5 min later. This approach worked very well for
Considered for Liquid-filled Capsules single-point quality control testing but would not be suit-
able for generating dissolution profiles. In many in-
Apparatus Type and Use of Sinkers stances involving hydrophobic drugs and fill materials
Agitation the only recourse may be to increase the dissolution time.
Medium Aqueous Some procedures for hydrophobic drugs have shown a
Sink conditions linear rate of dissolution that continues for up to 5 h (58).
Stability of the active in-
gredient Dissolution vs Disintegration
Buffer strength Historically, liquid-filled capsules have often employed
Counter-ion effect disintegration testing—or, more accurately, rupture test-
Surfactant Sink conditions ing—instead of dissolution testing. USP monographs for
Dispersion of the lipophi- calcifediol, chloral hydrate, cyclosporine, dronabinol,
lic fill and docusate sodium are a few examples. For solution-
filled capsules, especially those with a highly soluble drug
Compatibility
in a hydrophilic fill material, this may be a reasonable ap-
Medium pH Biorelevant proach (49). The active drug is already in solution, and
Enzymes Maximum activity at the the shell needs only to rupture to release the API. The
medium pH point at which the disintegration of a liquid-filled capsule
is considered complete is different from that of a solid do-
sage form. In order to disintegrate a tablet must fully
break apart and collapse into a loose pile of drug and ex-
UNIQUE ISSUES ASSOCIATED WITH LIQUID-FILLED cipients, whereas a liquid-filled capsule needs only to
CAPSULES: SUMMARY AND CONCLUSIONS rupture to meet the definition of disintegration. How-
ever, for capsules filled with a thick suspension or a waxy
The chemical and physical properties of liquid-filled
paste a simple rupture of the shell may not adequately
capsules pose unique challenges when formulators at-
demonstrate that the finished dosage form is delivering
tempt to develop dissolution methods, and this Stimuli
the drug in a suitable manner. Measures of the dispersion
article has reviewed some of these. One of the more com-
mon problems is pellicle formation and cross-linking of

# 2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
 STIMULI TO THE REVISION PROCESS
Pharmacopeial Forum Stimuli articles do not necessarily reflect the policies
Vol. 35(4) [July–Aug. 2009] of the USPC or the USP Council of Experts
and subsequent solubilization of the drug by the dissolu-
tion test also are required in order to evaluate the perfor-
mance of the dosage form.
A risk-based approach (56) can be applied to the appli-
cation of disintegration for testing the in vitro perfor-
mance of liquid-filled capsules. The suitability of the
disintegration test for this type of dosage form can be jus-
tified on the basis of the ICH Q6A decision tree #7 (76).
For some products Q6A supports the use of the disinte-
gration test instead of dissolution if the following condi-
tions are met: a) the drug is highly soluble between pH
1.2 and 6.8; b) the drug releases rapidly, i.e., more than
80% in 15 min at pH 1.2, 4.0, and 6.8; and c) a relation-
ship is established between dissolution and
disintegration.
Regulatory Aspects
To date FDA has not released any guidances specifi-
cally related to the design of dissolution and/or disinte-
gration tests for liquid-filled capsules. The FDA
guidance for dissolution testing of immediate-release so-
lid oral dosage forms (77) indicates the possible need for
enzymes to dissolve pellicles, if any are formed, to permit
drug dissolution, but it makes no other recommenda-
tions about this type of dosage form.
In USP XXII (1990), the sentence "Requirements for
Dissolution do not apply to soft gelatin capsules unless
otherwise specified in the monographs" was added to
Dissolution h711i. Pharmacopeial Forum 19(3) (1993) in-
cluded a proposal to delete that exemption, and the de-
letion became official in USP 23 (1995). Pharmacopeial
Forum 23(4) contained a proposal to add a rupture test
to all monographs for soft gelatin capsules. The mono-
graphs affected by this proposal were: Calcifediol Cap-
sules, Chloral Hydrate Capsules, Chlorotrianisene
Capsules, Clofazimine Capsules, Docusate Sodium Cap-
sules, Dronabinol Capsules, and Ethchlorovynol Cap-
sules. At that time the USP Subcommittee on
Dissolution and Bioavailability wanted to include a disso-
lution test in all monographs for soft gelatin capsules,
but, because of the inherent challenges associated with
the development of dissolution testing for this type of
dosage form, the Subcommittee proposed an interim
Dissolution rupture test that requires observation of the
rupture time for the capsule shell. The Subcommittee re-
ceived no suggestions regarding dissolution conditions
for these monographs and thus made the rupture test of-
ficial. This test can still be found in the following USP
monographs: Calcifediol Capsules, Chloral Hydrate Cap-
sules, Clofazimine Capsules, Cyclosporine Capsules, Doc-
usate Calcium Capsules, Docusate Sodium Capsules,
Docusate Potassium Capsules, Dronabinol Capsules, Er-
goloid Mesylate Capsules, Ethchlorovynol Capsules,
Cod Liver Oil Capsules, and Saw Palmetto Capsules.
The rupture test has been included in the USP General
Information Chapter Disintegration and Dissolution of
Dietary Supplements h2040i as a replacement of disinte-
gration for liquid-filled soft shell capsules that contain
dietary supplements (52, 54, 55).
# 2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
1039
REFERENCES
1. Ghebre-Sellassie I. Multiparticulate Oral Drug Delivery. New
York, NY: Marcel Dekker; 1994.
2. Walker SE, Bedford K, Eaves T. British patent 1.572.226. 30
July 1980.
3. McTaggart C, Wood R, Bedford K, Walker SE. The evalua-
tion of an automatic system for filling liquids into hard ge-
latin capsules. J Pharm Pharmacol. 1984;36:119–121.
4. Cuiné A, Mathis C, Stamm A, François D. Das Einbringen
viskoser Lösungen von Aktivstoffen in Hartgelatinekapseln.
Pharm. Ind. 1987;40(6):654–657.
5. Cole ET. Liquid-filled hard gelatin capsules. Pharm Technol
Int. 1989;1(5):29–33.
6. Wittwer F. New developments in hermetic sealing of hard
gelatin capsules. Pharm Manuf. 1985;2:24–27.
7. Bowtle WJ. Liquid filling of hard gelatin capsules: a new
technology for alternative formulations. Pharm Technol Eur-
ope. 1998;10:84–90.
8. Cadé D, Cole ET, Mayer JP, Wittwer F. Liquid-filled and
Stimuli to the Revision Process
sealed hard gelatin capsules. Acta Pharm Technol.
1987;33(2):97–100.
9. Cole ET. Liquid-filled and sealed hard gelatin capsule tech-
nologies. In: Rathbone MJ, Hadgraft J, Roberts MS, eds.
Modified-release Drug Delivery Technology. New York, NY:
Marcel Dekker; 2003:126,177–190.
10. USP. USP 31–NF 26, Pharmaceutical Dosage Forms h1151i.
Rockville, MD: US Pharmacopeial Convention; 2008:615–
626.
11. Jolley JE. The microstructure of gelatin binders. Photogr Sci
Eng. 1970;14(3):167–177.
12. USP. USP 31–NF 26. Rockville, MD: US Pharmacopeial Con-
vention; 2008:1139.
13. Bond CM, Lees KA, Packington JL. Cephalexin: a new oral
broad-spectrum antibiotic. Pharm J. 1970;205:210–214.
14. Kontny MJ, Mulski CA. Gelatin capsule brittleness as a func-
tion of relative humidity at room temperature. Int J Pharm.
1989;54:79–85.
15. Cadé D, Madit N. Liquid filling in hard gelatin capsules—
preliminary steps. B. T. Gattefossé. 1996;89:15–19.
16. C a r s t e n s e n J T, R h o d e s C R . D r u g D e v I n d Pha r m .
1993;83:915–921.
17. Digenis GA, Gold TB, Shah VP. Cross-linking of gelatin cap-
sules and its relevance to their in vitro–in vivo performance.
J Pharm Sci. 1994;83:915–921.
18. Schwier JR, Cooke GG, Hartauer KJ, Yu L. A reactive alde-
hyde capable of insolubilizing gelatin capsules. Pharm
Technol.1993;17:78–80.
19. Murthy KS, Enders NA, Fawzi MB. Dissolution stability of
hard-shell products. Part I. The effect of exaggerated stor-
age conditions. Pharm Technol.1989;13:72–84.
20. Murthy KS, Reisch RG, Fawzi MB. Dissolution stability of
hard-shell products. Part II. The effect of dissolution test
conditions on in vitro drug release. Pharm. Tech-
nol.1989;13:53–58.
21. Brown J, Madit. N, Cole ET, Wilding IR, Cadé D. The effect
of cross–linking on the in vivo disintegration of hard gelatin
capsules. Pharm Res. 1998;15:1026–1030.
22. Meyer MC, Straughn AB, Mhatre RM, et al. The effect of
gelatin cross-linking on the bioequivalence of hard and soft
gelatin acetaminophen capsules. Pharm Res.
2000;17:962–966.
 STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies
1040 of the USPC or the USP Council of Experts
23. USP. USP 31–NF 26, Dissolution h711i. Rockville, MD: US
Pharmacopeial Convention; 2008:267.
24. Ghirardi P, Catenazzo G, Mantero O, Merotti GC, Marzo A.
Bioavailability of digoxin in a new soluble pharmaceutical
formulation in capsules. J Pharm Sci. 1977;66(2):267–269.
25. Lahr W. Flüssig befüllte Hartgelatinekapseln. Pharm Ztg.
1986;131(15):871–874.
26. Herrmann R. Bioverfügbarkeit zweier neuer Nifedipin-For-
mulierungen. Pharm Ztg. 1986;131(15):869–870.
27. Lipinski CA. Strategies for optimizing oral drug delivery.
Kobe, April 19–21, 1999.
28. Robinson JR. Introduction: semi-solid formulations for oral
drug delivery. B. T. Gattefossé. 1996;189:11.
29. Kovarik JM, Mueller EA, Van-Bree JB, Tetzloff W, Kutz K. Re-
duced inter- and intraindividual variability in cyclosporin
pharmacokinetics from a microemulsion formulation. J
Pharm Sci.1994;83:444–446.
30. Meinzer A, Richter F, Vonderscher JF. Oil-free pharmaceuti-
cal compositions containing cyclosporin A. Patent WO 93/
20833. 1993.
Stimuli to the Revision Process
31. Walker SE, Ganley JA, Bedford K, Eaves T. The filling of mol-
ten and thixotropic formulations into hard gelatin cap-
sules. J Pharm Pharmacol.1980;32:389–393.
32. Howard JR, Gould PL. Drug release from thermosetting
fatty vehicles filled into hard gelatin capsules. Drug Dev
Ind Pharm.1987;13(6):1031–1045.
33. Bernasconi AC, Doelker E, Buri P. Diffusion and erosion con-
trolled drug release from lipid matrix formulations incorpo-
rated into hard gelatin capsules. Proc Int Symp Control Rel
Bioact Matr. 1985;12:272–273.
34. Dennis AB, Kellaway IW, Davidson R. Investigation of in-vi-
tro aging on in vivo release from a prolonged release liq-
uid-filled hard gelatin capsule formulation. Proc Int Symp
Control Rel Bioact Matr. 1988;15:390–391.
35. Seta Y, Higuchi F, Kawahara Y, Nishimura K, Okada R. De-
sign and preparation of captopril sustained-release dosage
forms and their biopharmaceutical properties. Int J
Pharm.1988;41:245—254.
36. Seta Y, Higushi F, Otsuka T, et al. Preparation and pharma-
cological evaluation of captopril sustained-release dosage
forms using oily semisolid matrix. Int J Pharm.
1988;41:255–262.
37. Seta Y, Otsuka T, Tokiwa H, et al. Design of captopril sus-
tained-release preparation with oily semisolid matrix in-
tended for use in human subjects. Int J Pharm.
1988;41:263–269.
38. Cole ET. Liquid-filled and sealed hard gelatin capsules. B. T.
Gattefossé. 1999;92:67–77.
39. Duerr M, Fridolin HU, Gneuss KD. Entwicklung von Rezep-
turen und Verfahren zur Abfüllung von flüssigen Massen in
Hartgelatinekapseln unter Produktionsbedingungen. Acta
Pharm Technol. 1983;29(3):245–251.
40. Lucas RA, Bowtle WJ, Ryden R. Disposition of vancomycin
in healthy volunteers from oral solution and semi-solid ma-
trix capsules. J Clin Pharm Ther.1987;12:27–31.
41. Bowtle WJ, Barker NJ, Wodhams J. A new approach to van-
comycin formulation using filling technology for semisolid
matrix capsules. Pharm Technol. 1988;12(6):86–97.
42. Doelker C, Doelker E, Buri P, Waginaire L. The incorporation
and in vitro release profile of liquid, deliquescent or un-
stable drugs with fusible excipients in hard gelatin cap-
sules. Drug Dev Ind Pharm. 1986;12(10):1553–1565.
# 2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
Vol. 35(4) [July–Aug. 2009]
43. Chatham SM. The use of bases in semi-solid matrix formu-
lations. S. T. P. Pharma. 1987;3(7):575–582.
44. Galal S, El-Massik M, Abdallah O, Daabis N. Formulation of
fast release glibenclamide liquid and semi-solid matrix
filled capsules. Acta Pharm. 2003;53:57–64.
45. Ofner CM III, Zhang Y, Jobeck VC, Bowman BJ. Crosslinking
studies in gelatin capsules treated with formaldehyde and
in capsules exposed to elevated temperature and humidity.
J Pharm Sci.2001;90(1):79–88.
46. Lozano R, et al. Gelatin cross-linking in capsules and its ef-
fect on dissolution. Am Pharm Rev. 2001;4(4):8–16.
47. Singh S, et al. Alteration in dissolution characteristics of ge-
latin-containing formulations. A review of the problem,
t e s t m e t h o d s , a n d s o l u t i o n s . P h a r m Te c h n o l .
2002;26(4):36–58.
48. Kenley RA, Chaudhry S, Visor, GC. Multidimensional col-
umn-switching liquid chromatographic method for disso-
lution testing of enprostil soft elastic gelatin capsules. J
Pharm Sci.1986;75(10):999–1002.
49. Pillay V, Fassihi R. A new method for dissolution studies of
lipid-filled capsules employing nifedipine as a model drug.
Pharm Res. 1999;16:333–337.
50. Wasan KM. Formulation and physiological and biopharma-
ceutical issues in the development of oral lipid-based drug
delivery systems. Drug Dev Ind Pharm. 2001;27:267–276.
51. Siewert M, et. al. FIP/AAPS guidelines to dissolution in vitro
release testing of novel/special dosage forms. AAPS
PharmSciTech. 2003;4:7.
52. Porter CJH, Charman, WN. In vitro assessment of oral lipid
based formulations. Adv Drug Del Dev. 2001;50:S127–
S147.
53. USP. USP 31–NF 26, Disintegration and Dissolution of Dietary
Supplements h2040i. Rockville, MD: US Pharmacopeial
Convention; 2008:732–736.
54. Humberstone, A J, Charman, WN. Lipid-based vehicles for
the oral delivery of poorly water soluble drugs. Adv Drug
Del Res.1997;25:103–128.
55. Pouton, CW. Formulation of self-emulsifying drug delivery
systems. Adv Drug Del Reviews. 1997;25:47–58.
56. Han JH, Gallery J. A risk based approach to in vitro perfor-
mance testing: a case study on the use of dissolution versus
disintegration for liquid filled soft gelatin capsules. Am
Pharm Rev. 2006;9(6):152–157.
57. FDA. Guidance for Industry–Dissolution Testing of Immediate
Release Solid Oral Dosage Forms. 1997. Available at
www.fda.gov/cder/guidance/1713bp1.pdf. Accessed 2
March 2009.
58. Noory C, Tran N, Ouderkirk L, Shah V. Steps for develop-
ment of a dissolution test for sparingly water-soluble drug
products. Dissol Technol. 2000;7(1):16–18.
59. Rohrs BR. Dissolution method development for poorly so-
luble compounds. Dissol Technol. 2001;8(3):6–12.
60. Marchais, H, et al. Cross-linking of hard gelatin carbamaze-
pine capsules: effect of dissolution conditions on in vitro
drug release. Eur J Pharm Sci. 2003;19:129–132
61. Savelli G, Spreti N, Di Profio P. Enzyme activity and stability
control by amphiphilic self-organizing systems in aqueous
solutions. Curr Opinion Coll Int Sci. 2000;5:111–117.
62. Maes P, Brusselmans J, Sereno A, Pitti C, Sonck M, Coffiner
M. In vitro and in vivo behavior of some liquid or semi-solid
filled hard gelatin capsules. B. T. Gattefosse, 1996;89:63–
69.
 STIMULI TO THE REVISION PROCESS
Pharmacopeial Forum Stimuli articles do not necessarily reflect the policies
Vol. 35(4) [July–Aug. 2009] of the USPC or the USP Council of Experts 1041
63. USP. USP 31–NF 26, Drug Release h724i. Rockville, MD: US 71. Burns SJ, et al. A study of enteric-coated liquid-filled hard
Pharmacopeial Convention; 2008:275–278. gelatin capsules with biphasic release characteristics. Int J
64. Bottom CB, Clark M, Carstensen, JT. Dissolution testing of Pharm. 1994;110:291–296.
soft shell capsules–acetaminophen and nifedipine. J Pharm 72. Moller H. Dissolution testing of different dosage forms
Sci. 1997;86(9):1057–1061. using the flow-through method. Pharm Ind.
65. El-Arini SK, Shiu GK, Skelly P. Theophylline-controlled re- 1983;45(6):617–622.
lease preparations and fatty food. An in vitro study using 73. Gjellan K, Graffner C. Comparative dissolution studies of
rotating dialysis cell method. Pharm Res. rectal formulations using the basket, the paddle and the
1990;7(11):1134–1140. flow-through methods. I—Paracetamol in suppositories
66. Takahashi M, et al. Studies on dissolution tests for soft ge- and soft gelatin capsules of both hydrophilic and lipophilic
latin capsules. IV. Dissolution test of nifedipine soft gelatin types. Acta Pharm Nord. 1989;1(6):343–354.
capsule containing water soluble vehicles by the rotating 74. Hu J, Kyad A, Ku V, Zhou P, Cauchon N. A comparison of
dialysis cell method. Chem Pharm Bull. 1994;42(2):333– dissolution testing on lipid soft gelatin capsules using USP
336. Apparatus 2 and Apparatus 4. Dissol Tech. 2005;12(2):6–9.
67. Takahashi, M, et al. Studies on dissolution tests of soft ge- 75. Aikman M, et al. Collaborative development of two-tier dis-
latin capsules. V. Rotating dialysis cell method. Chem Pharm solution testing for gelatin capsules and gelatin-coated
Bull. 1994;42(8):1672–1675. tablets using enzyme-containing media. Pharm Forum.
68. Takahashi M, et al. Studies on dissolution tests for soft ge- 1998;24(5):7045–7050.
latin capsules by the rotating dialysis cell (RDC) method. 76. ICH. Guidance on specifications: test procedure and ac-
VI. Preparation and evaluation of ibuprofen soft gelatin ceptance criteria for new drug substances and new drug

Stimuli to the Revision Process

capsule. Chem Pharm Bull. 1995;43(8):1398–1401.
69. Burns SJ, et al. Development and validation of an in vitro
dissolution method for a floating dosage form with bipha-
sic release characteristics. Int J Pharm. 1995;121:37–44.
70. Burns SJ, et al. Formulation strategies designed to maintain
the biphasic release characteristics of liquid-filled capsules.
Int J Pharm. 1996;141:9–16.
products: chemical substances, Q6A. Fed. Reg.
2000;65(251):83041–83063.
77. Gallery J, Han JH, Abraham C. Pepsin and pancreatin per-
formance in the dissolution of crosslinked gelatin capsules
from pH 1 to 8. Pharm Forum. 2004;30(3):1084–1089.

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